Abstract B04: NRF2 regulates serine biosynthesis in pancreatic ductal adenocarcinoma

Tumors have high energetic and anabolic needs for rapid growth and proliferation, and the serine biosynthetic pathway has recently been identified as an important source of metabolic intermediates for these processes. We recently demonstrated that a substantial fraction of NSCLC cell lines displayed significant serine/glycine biosynthetic activity due to KEAP1 and NRF2 mutations (DeNicola et al. Nature Genetics 2015). We demonstrated that NRF2 regulates glucose flux to serine by controlling transcription of serine biosynthetic genes through the transcription factor ATF4. Importantly, elevated expression of these genes conferred poor prognosis in human NSCLC. Thus, a substantial fraction of human NSCLC activates an NRF2-dependent transcriptional network that regulates serine and glycine metabolism and is linked to clinical aggressiveness. Pancreatic ductal adenocarcinoma (PDAC) also demonstrates high NRF2 activity due to mutations in KRAS and high MAPK signaling (DeNicola et al. Nature 2011). We demonstrate that serine biosynthesis enzyme expression is elevated in a mouse model of PDAC and that NRF2 regulates PHGDH expression in human PDAC cell lines. Furthermore, PDAC cell lines are resistant to serine starvation. PHGDH knockdown impairs the growth of tumor organoid orthotopic transplants, and the role of PHGDH in tumor maintenance is currently being investigated. These results suggest that the serine biosynthesis pathway is regulated by NRF2 in multiple cancers and may be an important therapeutic target. Citation Format: Gina M. DeNicola, Pei-Hsuan Chen, Edouard Mullarky, Christine Chio, John M. Asara, John D. Minna, David A. Tuveson, Ralph J. DeBerardinis, Lewis C. Cantley.{Authors}. NRF2 regulates serine biosynthesis in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B04.